My lab in Manchester has just released a fascinating research paper that touches on the lovely scientific elements of serendipity, hypothesis falsification and surprise results. This paper has continued the great scientific tradition of generating more questions than answers.
Have you ever wondered how does your body knows when it’s damaged? After your sprain your ankle your body launches into a full blown inflammatory response which clears the damaged tissue, kills any potential bugs and initiates the repair process. But how did the immune system detect the damage? The answer to this is rather complicated but it boils down to this, when tissue is damaged cells explode and this causes molecules that are normally only present in the cell to spew out into the surrounding fluid. Your immune cells have proteins called pattern recognition receptors which sniff the fluid checking to see if any of these intracellular molecules are in the extra-cellular fluid. When the pattern recognition receptors smell some damage they initiate alarm bells in the form of signalling chemicals called cytokines to bring more immune cells to the site of damage and activate the immune cells into action, essentially initiating inflammation. There are also pattern recognition receptors which sniff the extracellular fluid for molecules produced by infection like bacterial proteins. Inflammation is normally a good thing but in some situations it can be rather damaging such as chronic inflammation or hyper-inflammation in the brain. After stroke there is damaging inflammation and so what Dr. David Brough’s group was investigating was whether removing these pattern recognition receptors in mice using genetic engineering would reduce the amount of brain damage that happens after stroke. Now here comes the surprise- what they found was that removing the gene for the major pattern recognition receptor involved in recognizing cell damage had no effect on brain damage following stroke, however, removing either of the two major pattern recognition receptors involved in detecting infection related molecules did reduce brain damage following stroke. This creates a whole bunch of questions, which is the fun part of science, but here is our best guesses at what is going on- it could be that we’ve been wrong about exactly what molecules the infection pattern recognition receptors can detect (sniff out) perhaps they can detect others ones and these are important in inflammation of the brain. Or it could also be that by removing these receptors genetically we’ve completely changed the relationship between the trillions of bacteria in, on and around the body of the mice and this new relationship alters how the animal responded to the stroke. Or it could be (but seems less likely) normal background levels of bacteria are exacerbating stroke, and somehow the elimination of the host’s response to these bacteria reduces brain damage? It could also be several other things and that is fantastic! It means what got more science to do and more hypotheses to falsify. So I better get back in the lab.
AIM2 and NLRC4 inflammasomes contribute with ASC to acute brain injury independently of NLRP3